Novel pyrazolylquinazolinones as potassium channel openers

ABSTRACT

The present invention is directed to novel pyrazolylquinazolinone derivatives, pharmaceutical compositions containing them and their use in the treatment of disorders related to potassium channel.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application 60/774,696, filed on Feb. 17, 2006, which is incorporated by reference herein in its entirety.

FIELD OF THE INVENTION

The present invention is directed to novel pyrazolylquinazolinone derivatives, pharmaceutical compositions containing them and their use in the treatment of potassium channel related disorders. The compounds of the invention are thus useful for treatment of various disorders. These include but are not limited to urinary incontinence, overactive bladder, hypertension, erectile dysfunction, female sexual disorders, dysmenorrhea, irritable bowl syndrome, airway hyperactivity, epilepsy, stroke, Alzheimer's and Parkinson's diseases, myocardial injury and coronary artery disease, as well as hair loss and baldness.

BACKGROUND OF THE INVENTION

Ion channels play a fundamental role in the hormeostasis of cell function through the regulation of the transmembrane movement of ions. Cellular activity can be affected by modifications of the activities of the ion channels. This leads to changes in membrane potential difference. Potassium channels are a diverse and ubiquitous group of ion channels. They principally regulate the resting membrane potential of the cell and attenuate the level of excitation of cells. A functional KATP channel is a hetero-octamer assembled from four inward rectifying potassium channel subunits (Kir6.2) and four sulfonylurea receptor (SUR) subunits. There are two SUR genes, SUR1 and SUR2. SUR1/Kir6.2 channels are found in the pancreas and brain. Two major splice variants arise from the SUR2 gene, SUR2A and SUR2B, that differ only at the C-terminal 42 amino acids. SUR2A/Kir6.2 channels are found in cardiac and skeletal tissues whereas SUR2B/Kir6.2 channels are found in smooth muscles of many tissues including bladder (Aguilar-Bryan, 1998). A number of diseases or conditions may be treated with potassium channel openers. This includes overactive bladder, urinary incontinence, male erectile dysfunction, female sexual disorders, premature labor, benign prostate hyperplasia (BPH), dysmenorrhea, neurodegeneration, stroke, pain, coronary artery disease, angina, ischemia, eating disorders, irritable bowl syndrome and alopecia.

Urinary incontinence (UI) is a disease that can affect the overall quality of life of a patient. Overactive bladder (OAB) is the most prevalent form of UI, with reported prevalence rate from 40 to 70% of all diagnosed UI cases (Wein, 2000). OAB is characterized by the symptoms of increased urinary frequency, urgency, and involuntary loss of urine. A primary cause of OAB is an oversensitive bladder that contracts unexpectedly and involuntarily. The ideal pharmaceutical agent should suppress the involuntary contraction while leaving the normal voiding contractions intact. ATP-sensitive potassium channel openers (KCO) could serve as such agents. The ATP-sensitive potassium channels (KATP) are expressed in bladder smooth muscle and function as key regulators of the resting membrane potential in these cells. Compounds that selectively open these channels hyperpolarize the cell and decrease cellular excitability, resulting in suppression of involuntary bladder contractions, while leaving the normal micturition circuitry intact.

SUMMARY OF THE INVENTION

The invention is directed to compounds of formula I:

wherein:

R¹ is selected from the group consisting of hydrogen, halogen, carboxy, C₁₋₄ alkyl, halogenated C₁₋₄alkyl, —C(O)—C₁₋₄ alkyl, —C(O)-(halogenated C₁₋₄alkyl), —C(O)O—C₁₋₄alkyl, —S(O)₀₋₂—C₁₋₄alkyl, CN and NO₂;

R² is selected from the group consisting of hydrogen, halogen, carboxy, C₁₋₄ alkyl, halogenated C₁₋₄alkyl, —C(O)—C₁₋₄ alkyl, —C(O)-(halogenated C₁₋₄alkyl), —C(O)O—C₁₋₄alkyl, —S(O)₀₋₂-C₁₋₄alkyl, CN and NO₂;

R³ is selected from the group consisting of hydrogen, C₁₋₄ alkyl and halogenated C₁₋₄alkyl;

R⁴ is selected from the group consisting of hydrogen, carboxy, C₁₋₄ alkyl, halogenated C₁₋₄alkyl, aryl, heteroaryl, —C(O)-alkyl, —C(O)-(halogenated C₁₋₄alkyl) and —C(O)O—C₁₋₄alkyl;

wherein the aryl or heteroaryl whether alone or as part of a substituent group is optionally substituted with one or more substituents independently selected from the group consisting of halogen, C₁₋₄alkyl, C₁₋₄alkoxy, halogenated C₁₋₄alkyl, halogenated C₁₋₄alkoxy, cyano, nitro, —C(O)O—C₁₋₄alkyl and —S(O)₀₋₂-C₁₋₄alkyl;

or a pharmaceutically acceptable salt thereof.

It will be appreciated that the compounds of formula (I) can exists as tautomers. Those skilled in the art will recognized that when N(1) and C(2) form a double bond, then C(2) and N(3) form a single bond. In the other tautomeric form when N(1) and C(2) form a single bond, then C(2) and N(3) form a double bond. In this latter tautomeric form, the H atom illustrated as bonded to N(3) will, of course, be bonded to N(1).

Illustrative of the invention is a pharmaceutical composition comprising a pharmaceutically acceptable carrier and any of the compounds described above. An illustration of the invention is a pharmaceutical composition made by mixing any of the compounds described above and a pharmaceutically acceptable carrier. Illustrating the invention is a process for making a pharmaceutical composition comprising mixing any of the compounds described above and a pharmaceutically acceptable carrier.

Exemplifying the invention are methods of treating disorders related to ion channels, preferably a potassium ion channel, more preferably an ATP-sensitive potassium ion channel, comprising administering, to a subject in need thereof, a therapeutically effective amount of any of the compounds or pharmaceutical compositions described above.

An example of the invention is a method for treating a disorder selected from the group consisting of urinary incontinence, overactive bladder, hypertension, erectile dysfunction, female sexual disorders, dysmenorrhea, irritable bowl syndrome, airway hyperactivity, epilepsy, stroke, Alzheimer's disease, Parkinson's disease, myocardial injury, coronary artery disease, hair loss and baldness, preferably urinary incontinence, comprising administering, to a subject in need thereof, an effective amount of any of the compounds or pharmaceutical compositions described above.

Another example of the invention is the use of any of the compounds described herein in the preparation of a medicament for treating: (a) urinary incontinence, (b) overactive bladder, (c) hypertension, (d) erectile dysfunction, (e) female sexual disorders, (f) dysmenorrhea, (g) irritable bowl syndrome, (h) airway hyperactivity, (i) epilepsy, (j) stroke, (k) Alzheimer's disease, (l) Parkinson's disease, (m) myocardial injury, (n) coronary artery disease, (o) hair loss or (p) baldness, in a subject in need thereof.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is directed to compounds of formula (I)

wherein R¹, R², R³ and R⁴ are as herein defined. The compounds of the present invention are potassium channels openers. The compounds of the present are thus useful for treatment of various disorders including, but not limited to, urinary incontinence, overactive bladder, hypertension, erectile dysfunction, female sexual disorders, dysmenorrhea, irritable bowl syndrome, airway hyperactivity, epilepsy, stroke, Alzheimer's and Parkinson's diseases, myocardial injury, coronary artery disease as well as hair loss and baldness. Preferably, the compounds of the present invention are useful in the treatment of urinary incontinence or overactive bladder.

As used herein, “halogen” shall mean chlorine, bromine, fluorine and iodine. Preferably, the halogen is chlorine, bromine or fluorine, more preferably, chlorine or fluorine.

As used herein, the term “alkyl” whether used alone or as part of a substituent group, include straight and branched chains. For example, alkyl radicals include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, pentyl and the like. Similarly, the term “C₁₋₄alkyl” whether used alone or as part of a substituent group, include straight and branched chains containing 4 carbon atoms. For example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and t-butyl.

As used herein, unless otherwise noted, “alkoxy” whether used alone or as part of a substituent group, shall denote an oxygen ether radical of the above described straight or branched chain alkyl groups. For example, methoxy, ethoxy, n-propoxy, sec-butoxy, t-butoxy, n-hexyloxy and the like. Similarly, the term “C₁₋₄alkoxy” whether used alone or as part of a substituent group, shall denote an oxygen ether radical of the above described straight or branched chain C₁₋₄alkyl groups. For example, methoxy, ethoxy, n-propoxy, sec-butoxy, t-butoxy, and the like.

As used herein, unless otherwise noted, the term “halogen substituted C₁₋₄alkyl” shall mean any C₁₋₄alkyl group as defined above substituted with at least one halogen atom, preferably substituted with a least one fluoro atom. Suitable examples include but are not limited to —CF₃, —CHF₂, —CH₂—CF₃, —CF₂—CF₂—CF₂—CF₃, and the like. Similarly, as used herein, unless otherwise noted, the term “halogen substituted C₁₋₄alkoxy” shall mean any C₁₋₄alkoxy group as defined above substituted with at least one halogen atom, preferably substituted with a least one fluoro atom. Suitable examples include but are not limited to —OCF₃, —OCHF₂, —OCH₂—CF₃, —OCF₂—CF₂—CF₂—CF₃, and the like.

As used herein, unless otherwise noted, “aryl” shall refer to unsubstituted carbocylic aromatic groups such as phenyl, naphthyl, and the like. Preferably, the aryl group is phenyl or naphthyl, more preferably, phenyl.

As used herein, unless otherwise noted, the term “partially unsaturated” when referring to a ring structure shall mean that the ring structure is stable and contains at least one unsaturated bond (i.e. at least one double bond). Suitable examples include, but are not limited to cyclohexenyl, and the like.

As used herein, unless otherwise noted, “heteroaryl” shall denote any five or six membered monocyclic aromatic ring structure containing at least one heteroatom selected from the group consisting of O, N and S, optionally containing one to three additional heteroatoms independently selected from the group consisting of O, N and S; or a nine or ten membered bicyclic aromatic ring structure containing at least one heteroatom selected from the group consisting of O, N and S, optionally containing one to four additional heteroatoms independently selected from the group consisting of O, N and S. The heteroaryl group may be attached at any heteroatom or carbon atom of the ring such that the result is a stable structure.

Examples of suitable heteroaryl groups include, but are not limited to, pyrrolyl, furyl, thienyl, oxazolyl, imidazolyl, purazolyl, isoxazolyl, isothiazolyl, triazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyranyl, furazanyl, indolizinyl, indolyl, isoindolinyl, indazolyl, benzofuryl, benzothienyl, benzimidazolyl, benzthiazolyl, purinyl, quinolizinyl, quinolinyl, isoquinolinyl, isothiazolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, and the like.

As used herein, the term “heterocycloalkyl” shall denote any five to seven membered monocyclic, saturated or partially unsaturated ring structure containing at least one heteroatom selected from the group consisting of O, N and S, optionally containing one to three additional heteroatoms independently selected from the group consisting of O, N and S; or a nine to ten membered saturated, partially unsaturated or partially aromatic bicyclic ring system containing at least one heteroatom selected from the group consisting of O, N and S, optionally containing one to four additional heteroatoms independently selected from the group consisting of O, N and S. The heterocycloalkyl group may be attached at any heteroatom or carbon atom of the ring such that the result is a stable structure.

Examples of suitable heterocycloalkyl groups include, but are not limited to, pyrrolinyl, pyrrolidinyl, dioxalanyl, imidazolinyl, imidazolidinyl, pyrazolinyl, pyrazolidinyl, piperidinyl, dioxanyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, trithianyl, indolinyl, chromenyl, 3,4-methylenedioxyphenyl, 2,3-dihydrobenzofuryl, and the like.

As used herein, unless otherwise noted, the term “heteocyclyI” shall mean any heteroaryl or heterocyclyl group, as defined above. Preferably, the heterocyclyl group comprises at least one nitrogen atom. More preferably, the heterocyclyl group comprises one to three heteroatoms independently selected from the group consisting of O, S and N. More preferably still, the heterocyclyl group comprises one to two heteroatoms independently selected from the group consisting of O, S and N. Preferably, the heterocyclyl group comprises one N atom and further comprises one additional heteroatom independently selected from the group consisting of O, S and N. Preferably, the heterocyclyl group is saturated, aromatic or partially aromatic, more preferably, the heterocyclyl group is aromatic or benzo-fused.

Preferably, the heterocyclyl is selected from the group consisting of 4,5-dihydro-oxazolyl, piperidiny, imidazolyl, pyrimidinyl, pyrazolyl, pyrazolinyl, pyridazinyl, indolinyl, indazolyl, isoindolyl, pyrrolo[3,4-c]pyridinyl, benzimidazolyl, benzoisothiazolyl, benzoisoxazolyl, benzthiazolyl, benzoxazolyl, quinazolinyl, quinolinyl and isoquinolinyl.

As used herein, the notation “*” shall denote the presence of a stereogenic center.

When a particular group is “substituted” (e.g., aryl, heterocycloalkyl, heteroaryl), that group may have one or more substituents, preferably from one to five substituents, more preferably from one to three substituents, most preferably from one to two substituents, independently selected from the list of substituents.

With reference to substituents, the term “independently” means that when more than one of such substituents is possible, such substituents may be the same or different from each other.

To provide a more concise description, some of the quantitative expressions given herein are not qualified with the term “about”. It is understood that whether the term “about” is used explicitly or not, every quantity given herein is meant to refer to the actual given value, and it is also meant to refer to the approximation to such given value that would reasonably be inferred based on the ordinary skill in the art, including approximations due to the experimental and/or measurement conditions for such given value.

As used herein, unless otherwise noted, the term “leaving group” shall mean a charged or uncharged atom or group which departs during a substitution or displacement reaction. Suitable examples include, but are not limited to, Br, Cl, I, mesylate, tosylate, and the like.

As used herein, unless otherwise noted, the term “nitrogen protecting group” shall mean a group which may be attached to a nitrogen atom to protect said nitrogen atom from participating in a reaction and which may be readily removed following the reaction. Suitable nitrogen protecting groups include, but are not limited to carbamates—groups of the formula —C(O)O—R wherein R is for example methyl, ethyl, t-butyl, benzyl, phenylethyl, CH₂═CH—CH₂—, and the like; amides—groups of the formula —C(O)—R′ wherein R′ is for example methyl, phenyl, trifluoromethyl, and the like; N-sulfonyl derivatives—groups of the formula —SO₂—R″ wherein R″ is for example tolyl, phenyl, trifluoromethyl, 2,2,5,7,8-pentamethylchroman-6-yl-, 2,3,6-trimethyl-4-methoxybenzene, and the like. Other suitable nitrogen protecting groups may be found in texts such as T. W. Greene & P. G. M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991.

Under standard nomenclature used throughout this disclosure, the terminal portion of the designated side chain is described first, followed by the adjacent functionality toward the point of attachment. Thus, for example, a “phenyl-C₁₋₄alkyl-amino-carbonyl-C₁₋₄alkyl-” substituent refers to a group of the formula

Abbreviations used in the specification, particularly the Schemes and Examples, are as follows: p DCM=Dichloromethane

DMAC=Dimethylacetamide

DMF=N,N-Dimethylformamide

DMSO=Dimethylsulfoxide

Et=Ethyl (i.e —CH₂CH₃)

Etl=Ethyl Iodine

EtOAc=Ethyl acetate

HPLC=High Pressure Liquid Chromatography

KO-t-Bu or t-Bu-OK=Potassium t-butoxide

Me=Methyl (i.e. —CH₃)

Mel=Methyl Iodide

MeOH=Methanol

NaOAc=Sodium Acetate

TEA or Et₃N=Triethylamine

THF=Tetrahydrofuran

The term “subject” as used herein, refers to an animal, preferably a mammal, most preferably a human, who has been the object of treatment, observation or experiment.

The term “therapeutically effective amount” as used herein, means that amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician, which includes alleviation of the symptoms of the disease or disorder being treated.

As used herein, the term “composition” is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combinations of the specified ingredients in the specified amounts.

Where the compounds according to this invention have at least one chiral center, they may accordingly exist as enantiomers. Where the compounds possess two or more chiral centers, they may additionally exist as diastereomers. It is to be understood that all such isomers and mixtures thereof are encompassed within the scope of the present invention. Furthermore, some of the crystalline forms for the compounds may exist as polymorphs and as such are intended to be included in the present invention. In addition, some of the compounds may form solvates with water (i.e., hydrates) or common organic solvents, and such solvates are also intended to be encompassed within the scope of this invention.

The present invention includes within its scope “prodrugs” of the compounds of this invention. In general, such prodrugs will be functional derivatives of the compounds which are readily convertible in vivo into the required compound. Thus, in the methods of treatment of the present invention, the term “administering” shall encompass the treatment of the various disorders described with the compound specifically disclosed or with a compound which may not be specifically disclosed, but which converts to the specified compound in vivo after administration to the patient. Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in “Design of Prodrugs”, ed. H. Bundgaard, Elsevier, 1985.

The present invention includes within its scope “pharmaceutically acceptable salts” of the compounds of this invention. For use in medicine, the salts of the compounds of this invention refer to non-toxic pharmaceutically acceptable salts. Other salts may, however, be useful in the preparation of compounds according to this invention or of their pharmaceutically acceptable salts. Suitable pharmaceutically acceptable salts of the compounds include acid addition salts which may, for example, be formed by mixing a solution of the compound with a solution of a pharmaceutically acceptable acid such as hydrochloric acid, sulfuric acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid, citric acid, tartaric acid, carbonic acid or phosphoric acid. Furthermore, where the compounds of the invention carry an acidic moiety, suitable pharmaceutically acceptable salts thereof may include alkali metal salts, e.g., sodium or potassium salts; alkaline earth metal salts, e.g., calcium or magnesium salts; and salts formed with suitable organic ligands, e.g., quaternary ammonium salts. Thus, representative pharmaceutically acceptable salts include the following:

acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, calcium edetate, camsylate, carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate, N-methylglucamine ammonium salt, oleate, pamoate (embonate), palmitate, pantothenate, phosphate/diphosphate, polygalacturonate, salicylate, stearate, sulfate, subacetate, succinate, tannate, tartrate, teoclate, tosylate, triethiodide and valerate.

Representative acids and bases which may be used in the preparation of pharmaceutically acceptable salts include the following:

acids including acetic acid, 2,2-dichloroactic acid, acylated amino acids, adipic acid, alginic acid, ascorbic acid, L-aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, (+)-camphoric acid, camphorsulfonic acid, (+)-(1S)-camphor-10-sulfonic acid, capric acid, caproic acid, caprylic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydrocy-ethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid, D-gluconic acid, D-glucoronic acid, L-glutamic acid, α-oxo-glutaric acid, glycolic acid, hipuric acid, hydrobromic acid, hydrochloric acid, (+)-L-lactic acid, (±)-DL-lactic acid, lactobionic acid, maleic acid, (−)-L-malic acid, malonic acid, (±)-DL-mandelic acid, methanesulfonic acid, naphthalene-2-sulfonic acid, naphthalene-1,5-disulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinc acid, nitric acid, oleic acid, orotic acid, oxalic acid, palmitric acid, pamoic acid, phosphoric acid, L-pyroglutamic acid, salicylic acid, 4-amino-salicylic acid, sebaic acid, stearic acid, succinic acid, sulfuric acid, tannic acid, (+)-L-tartaric acid, thiocyanic acid, p-toluenesulfonic acid and undecylenic acid; and

bases including ammonia, L-arginine, benethamine, benzathine, calcium hydroxide, choline, deanol, diethanolamine, diethylamine, 2-(diethylamino)-ethanol, ethanolamine, ethylenediamine, N-methyl-glucamine, hydrabamine, 1H-imidazole, L-lysine, magnesium hydroxide, 4-(2-hydroxyethyl)-morpholine, piperazine, potassium hydroxide, 1-(2-hydroxyethyl)-pyrrolidine, secondary amine, sodium hydroxide, triethanolamine, tromethamine and zinc hydroxide.

In an embodiment of the present invention, R¹ is selected from the group consisting of hydrogen, halogen, C₁₋₄ alkyl, halogenated C₁₋₄alkyl, CN and NO₂. In another embodiment of the present invention, R¹ is selected from the group consisting of hydrogen, halogen, halogenated C₁₋₄alkyl and cyano. In another embodiment of the present invention, R¹ is selected from the group consisting of hydrogen, bromo, chloro and cyano. In another embodiment of the present invention, R¹ is bromo and chloro.

In an embodiment of the present invention, R² is selected from the group consisting of hydrogen, halogen, C₁₋₄ alkyl, halogenated C₁₋₄alkyl, CN and NO₂. In another embodiment of the present invention, R² is selected from the group consisting of hydrogen, halogen and halogenated C₁₋₄alkyl. In another embodiment of the present invention, R² is selected from the group consisting of hydrogen and halogenated C₁₋₄alkyl. In another embodiment of the present invention, R² is selected from the group consisting of hydrogen and trifluoromethyl.

In an embodiment of the present invention, R³ is selected from the group consisting of hydrogen, C₁₋₄alkyl and halogenated C₁₋₄alkyl. In another embodiment of the present invention, R³ is C₁₋₄alkyl. In another embodiment of the present invention, R³ is methyl.

In an embodiment of the present invention, R⁴ is selected from the group consisting of hydrogen, carboxy, C₁₋₄ alkyl, halogenated C₁₋₄alkyl, phenyl and —C(O)O—C₁₋₄alkyl. In another embodiment of the present invention, R⁴ is hydrogen, C₁₋₄alkyl and C(O)O—C₁₋₄alkyl. In another embodiment of the present invention, R³ is hydrogen and C(O)O-Et.

Additional embodiments of the present invention, include those wherein the substituents selected for one or more of the variables defined herein (i.e. R¹, R², R³ and n) are independently selected to be any individual substituent or any subset of substituents selected from the complete list as defined herein.

Representative compounds of the present invention are as listed in Tables 1 below.

TABLE 1 Compounds of Formula (I) ID R¹ R² R³ R⁴ 1 Cl H Me H 2 Br H Me H 3 H CF₃ Me H 4 Cl H Me C(O)—O-Et

Synthesis

Compounds of formula (I) may be prepared according to the process outlined in Scheme 1.

Accordingly, a suitably substituted compound of formula (II), a known compound or compound prepared by known methods is reacted with a suitably substituted (III), known compounds, in the presence of a base such as TEA, DIPEA, and the like, in an organic solvent such DCM, THF, and the like, preferably at a temperature in the range of from about 0° C. and room temperature, more preferably at a temperature of 0° C., to yield the corresponding compound of formula (IX).

The compound of formula (IX) is treated with a base, such as ammonia hydroxide, sodium hydride, and the like, in an organic solvent such as ethanol, methanol, THF, and the like, at a temperature in the range of from about 50° C. and about 80° C., to yield the corresponding compounds of formula (X).

The compound of formula (X) is treated with a diazo source R₄CHN₂, a known compound or compound prepared by known methods, such as TMS diazomethane, diazo ethyl acetate and the like, in an organic solvent such as ether, THF, dioxane and the like, at a temperature in the range of from about 50° C. and 80° C., to yield the corresponding compounds of formula (I).

During any of the processes for preparation of the compounds of the present invention, it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned. This may be achieved by means of conventional protecting groups, such as those described in Protective Groups in Organic Chemistry, ed. J.F.W. McOmie, Plenum Press, 1973; and T.W. Greene & P.G.M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991. The protecting groups may be removed at a convenient subsequent stage using methods known from the art.

One skilled in the art will recognize that wherein a reaction step of the present invention may be carried out in a variety of solvents or solvent systems, said reaction step may also be carried out in a mixture of the suitable solvents or solvent systems.

The present invention further comprises pharmaceutical compositions containing one or more compounds of formula (I) with a pharmaceutically acceptable carrier. Pharmaceutical compositions containing one or more of the compounds of the invention described herein as the active ingredient can be prepared by intimately mixing the compound or compounds with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques. The carrier may take a wide variety of forms depending upon the desired route of administration (e.g., oral, parenteral). Thus for liquid oral preparations such as suspensions, elixirs and solutions, suitable carriers and additives include water, glycols, oils, alcohols, flavoring agents, preservatives, stabilizers, coloring agents and the like; for solid oral preparations, such as powders, capsules and tablets, suitable carriers and additives include starches, sugars, diluents, granulating agents, lubricants, binders, disintegrating agents and the like. Solid oral preparations may also be coated with substances such as sugars or be enteric-coated so as to modulate major site of absorption. For parenteral administration, the carrier will usually consist of sterile water and other ingredients may be added to increase solubility or preservation. Injectable suspensions or solutions may also be prepared utilizing aqueous carriers along with appropriate additives.

To prepare the pharmaceutical compositions of this invention, one or more of the compounds of the present invention selected as the active ingredient is intimately admixed with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques, which carrier may take a wide variety of forms depending of the form of preparation desired for administration, e.g., oral or parenteral such as intramuscular. In preparing the compositions in oral dosage form, any of the usual pharmaceutical media may be employed. Thus, for liquid oral preparations, such as for example, suspensions, elixirs and solutions, suitable carriers and additives include water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like; for solid oral preparations such as, for example, powders, capsules, caplets, gelcaps and tablets, suitable carriers and additives include starches, sugars, diluents, granulating agents, lubricants, binders, disintegrating agents and the like. Because of their ease in administration, tablets and capsules represent the most advantageous oral dosage unit form, in which case solid pharmaceutical carriers are obviously employed. If desired, tablets may be sugar coated or enteric coated by standard techniques. For parenterals, the carrier will usually comprise sterile water, through other ingredients, for example, for purposes such as aiding solubility or for preservation, may be included. Injectable suspensions may also be prepared, in which case appropriate liquid carriers, suspending agents and the like may be employed. The pharmaceutical compositions herein will contain, per dosage unit, e.g., tablet, capsule, powder, injection, teaspoonful and the like, an amount of the active ingredient necessary to deliver an effective dose as described above. The pharmaceutical compositions herein will contain, per unit dosage unit, e.g., tablet, capsule, powder, injection, suppository, teaspoonful and the like, of from about 50-100 mg and may be given at a dosage of from about 0.5-5.0 mg/kg/day, preferably from about 1.0-3.0 mg/kg/day. The dosages, however, may be varied depending upon the requirement of the patients, the severity of the condition being treated and the compound being employed. The use of either daily administration or post-periodic dosing may be employed.

Preferably these compositions are in unit dosage forms from such as tablets, pills, capsules, powders, granules, sterile parenteral solutions or suspensions, metered aerosol or liquid sprays, drops, ampoules, autoinjector devices or suppositories; for oral parenteral, intranasal, sublingual or rectal administration, or for administration by inhalation or insufflation. Alternatively, the composition may be presented in a form suitable for once-weekly or once-monthly administration; for example, an insoluble salt of the active compound, such as the decanoate salt, may be adapted to provide a depot preparation for intramuscular injection. For preparing solid compositions such as tablets, the principal active ingredient is mixed with a pharmaceutical carrier, e.g. conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, and other pharmaceutical diluents, e.g. water, to form a solid preformulation composition containing a homogeneous mixture of a compound of the present invention, or a pharmaceutically acceptable salt thereof. When referring to these preformulation compositions as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective dosage forms such as tablets, pills and capsules. This solid preformulation composition is then subdivided into unit dosage forms of the type described above containing from 0.1 to about 500 mg of the active ingredient of the present invention. The tablets or pills of the novel composition can be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action. For example, the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former. The two components can be separated by an enteric layer which serves to resist disintegration in the stomach and permits the inner component to pass intact into the duodenum or to be delayed in release. A variety of material can be used for such enteric layers or coatings, such materials including a number of polymeric acids with such materials as shellac, cetyl alcohol and cellulose acetate.

The liquid forms in which the novel compositions of the present invention may be incorporated for administration orally or by injection include, aqueous solutions, suitably flavored syrups, aqueous or oil suspensions, and flavored emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil or peanut oil, as well as elixirs and similar pharmaceutical vehicles. Suitable dispersing or suspending agents for aqueous suspensions, include synthetic and natural gums such as tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose, methylcellulose, polyvinyl-pyrrolidone or gelatin.

The method of treating disorders related to ion channels, for example potassium ion channels, described in the present invention may also be carried out using a pharmaceutical composition comprising any of the compounds as defined herein and a pharmaceutically acceptable carrier. The pharmaceutical composition may contain between about 0.01 mg and 1000 mg, preferably about 1 to 500 mg, more preferably, 10 to 100 mg of the compound, and may be constituted into any form suitable for the mode of administration selected. Carriers include necessary and inert pharmaceutical excipients, including, but not limited to, binders, suspending agents, lubricants, flavorants, sweeteners, preservatives, dyes, and coatings. Compositions suitable for oral administration include solid forms, such as pills, tablets, caplets, capsules (each including immediate release, timed release and sustained release formulations), granules, and powders, and liquid forms, such as solutions, syrups, elixers, emulsions, and suspensions. Forms useful for parenteral administration include sterile solutions, emulsions and suspensions.

Advantageously, compounds of the present invention may be administered in a single daily dose, or the total daily dosage may be administered in divided doses of two, three or four times daily. Furthermore, compounds for the present invention can be administered in intranasal form via topical use of suitable intranasal vehicles, or via transdermal skin patches well known to those of ordinary skill in that art. To be administered in the form of a transdermal delivery system, the dosage administration will, of course, be continuous rather than intermittent throughout the dosage regimen.

For instance, for oral administration in the form of a tablet or capsule, the active drug component can be combined with an oral, non-toxic pharmaceutically acceptable inert carrier such as ethanol, glycerol, water and the like. Moreover, when desired or necessary, suitable binders; lubricants, disintegrating agents and coloring agents can also be incorporated into the mixture. Suitable binders include, without limitation, starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like. Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum and the like.

The liquid forms in suitably flavored suspending or dispersing agents such as the synthetic and natural gums, for example, tragacanth, acacia, methyl-cellulose and the like. For parenteral administration, sterile suspensions and solutions are desired. Isotonic preparations which generally contain suitable preservatives are employed when intravenous administration is desired.

The compound of the present invention can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles, and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine or phophatidylcholines.

Compounds of the present invention may also be delivered by the use of monoclonal antibodies as individual carriers to which the compound molecules are coupled. The compounds of the present invention may also be coupled with soluble polymers as targetable drug carriers. Such polymers can include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamidephenol, polyhydroxy-ethylaspartamidephenol, or polyethyl eneoxidepolylysine substituted with palmitoyl residue. Furthermore, the compounds of the present invention may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polyepsilon caprolactone, polyhydroxy butyeric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and cross-linked or amphipathic block copolymers of hydrogels.

Compounds of this invention may be administered in any of the foregoing compositions and according to dosage regimens established in the art whenever treatment of disorders related to ion channels, for example potassium ion channels, is required.

The daily dosage of the products may be varied over a wide range from 0.01 to 1,000 mg per adult human per day. For oral administration, the compositions are preferably provided in the form of tablets containing, 0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 100,150, 200, 250, 500 and 1000 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated. An effective amount of the drug is ordinarily supplied at a dosage level of from about 0.01 mg/kg to about 300 mg/kg of body weight per day. Preferably, the range is from about 0.5 to about 5.0 mg/kg of body weight per day, most preferably, from about 1.0 to about 3.0 mg/kg of body weight per day. The compounds may be administered on a regimen of 1 to 4 times per day.

Optimal dosages to be administered may be readily determined by those skilled in the art, and will vary with the particular compound used, the mode of administration, the strength of the preparation, the mode of administration, and the advancement of the disease condition. In addition, factors associated with the particular patient being treated, including patient age, weight, diet and time of administration, will result in the need to adjust dosages.

The following Examples are set forth to aid in the understanding of the invention, and are not intended and should not be construed to limit in any way the invention set forth in the claims which follow thereafter.

In the Examples which follow, some synthesis products are listed as having been isolated as a residue. It will be understood by one of ordinary skill in the art that the term “residue” does not limit the physical state in which the product was isolated and may include, for example, a solid, an oil, a foam, a gum, a syrup, and the like.

EXAMPLE 1 5-Chloro-2-(2-methyl-acryloylamino)-benzamide

2-Amino-5-chloro-benzamide (2.5 mmoL), a literature known compound, was treated with TEA (3.0 mmoL) followed by methylacryl chloride (2.5 mmoL) in DCM at 0 oC. The reaction was slowly warmed to room temperature and kept for another 2 h. The reaction mixture was then partitioned between DCM and water. The organic layer was washed with sat. Na₂CO₃, brine, dried over anhydrous Na₂SO₄, filtered, concentrated and purified by silica gel column chromatography to afford the title compound as a white solid.

¹H NMR: (CDCl₃) δ 8.70 (d, J=7.5 Hz, 1 H), 7.52 (s, 1H), 7.44 (d, J=7.5 Hz, 1H), 6.60 (br, s, 2H), 6.05 (br, s, 1H), 6.00 (s, 1H), 5.51 (s, 1H), 2.05 (s, 3H). MS (m/z): MH⁺239.

EXAMPLE 2 5-Bromo-2-(2-methyl-acryloylamino)-benzamide

Following the procedure described in the Example 1, using 2-amino-5-chloro-benzamide as starting material to yield the title compound as a white solid.

¹H NMR: (CDCl₃) δ 8.65 (d, J=7.5 Hz, 1H), 7.65 (s, 1H), 7.60 (d, J=7.5 Hz, 1H), 6.40 (br, s, 2H), 6.00 (s, 1H), 5.91 (br, s, 1H), 5.55 (s, 1H), 2.10 (s, 3H).

MS (m/z): MH⁺284.

EXAMPLE 3 2-(2-Methyl-acryloylamino)-4-trifluoromethyl-benzamide

Following the procedure described in the Example 1, using 2-amino-4-trifluoromethyl-benzamide as starting material to yield the title compound as a white solid.

¹H NMR: (CDCl₃) δ 9.05 (s, 1H), 7.65 (d, J=8.0 Hz, 1H), 7.30 (d, J=7.5 Hz, 1H), 6.50 (br, s, 1H), 6.00 (s, 1H), 5.91 (br, s, 1H), 5.55 (s, 1H), 2.10 (s, 3H).

MS (m/z): MH⁺273.

EXAMPLE 4 6-Chloro-2-isopropenyl-3H-quinazolin-4-one

5-Chloro-2-(2-methyl-acryloylamino)-benzamide (1.5 mmoL) in EtOH (10 mL) was treated with ammonia hydroxide (˜3.0 mmoL) at 80° C. for 4 h. The reaction was then cooled down and the solvent was removed. The reaction mixture was then partitioned between DCM and water. The organic layer was washed with sat. NH₄Cl, brine, dried over anhydrous Na₂SO₄, filtered, concentrated and purified by silica gel column chromatography to afford the title compound as a white solid.

¹H NMR: (CDCl₃) δ 8.45 (s, 1H), 8.20 (d, J=8.5 Hz, 1H), 7.75 (br, s, 1H), 7.30 (d, J=8.5 Hz, 1H), 5.85 (s, 1H), 5.55 (s, 1H), 2.05 (s, 3H). MS (m/z): MH⁺221.

EXAMPLE 5 6-Bromo-2-isopropenyl-3H-quinazolin-4-one

Following the procedure described in the Example 4, using 5-bromo-2-(2-methyl-acryloylamino)-benzamide as starting material to yield the title compound as a white solid.

¹H NMR: (CDCl₃) δ 10.50 (br, s, 1H), 8.40 (s, 1H), 7.85 (d, J=7.5 Hz, 1H), 7.62 (d, J=7.5 Hz, 1H), 6.05 (s, 1H), 5.71 (s, 1H), 2.25 (s, 3H). MS (m/z):

MH⁺266.

EXAMPLE 6 2-Isopropenyl-7-trifluoromethyl-3H-quinazolin-4-one

Following the procedure described in the Example 4, using 2-(2-Methyl-acryloylamino)-4-trifluoromethyl-benzamide as starting material to yield the title compound as a white solid.

¹H NMR: (CDCl₃) δ 7.56 (d, J=8.0 Hz, 1H), 7.25 (d, J=7.5 Hz, 1H), 6.70 (br, s, 1H), 6.10 (s, 1H), 5.71 (s, 1H), 2.25 (s, 3H). MS (m/z): MH⁺255.

EXAMPLE 7 6-Chloro-2-(3-methyl-3,4-dihydro-2H-pyrazol-3-vi)-3H-quinazolin-4-one

6-Chloro-2-isopropenyl-3H-quinazolin-4-one (1 mmoL) in THF (5 mL) was treated with TMSCHN₂ (1.0 N, 3.0 mmoL) at 50° C. for 4 h. The solvent was removed and the residue was purified by silica gel column chromatography to yield the title compound as a white solid.

¹H NMR: (CDCl₃) δ 10.61 (br, s, 1H), 8.21 (s, 1H), 7.65 (d, J=6.5 Hz, 1H), 7.60 (d, J=7.5 Hz, 1H), 6.81(br, s, 1H), 3.15 (abq, J=12.5 Hz, 2H), 1.70 (s, 3H).

MS (m/z): MH⁺263.

EXAMPLE 8 6-Bromo-2-(3-methyl-3,4-dihydro-2H-pyrazol-3-vi)-3H-quinazolin-4-one

Following the procedure described in the Example 7, using 6-bromo-2-isopropenyl-3H-quinazolin-4-one and TMSCHN₂ as starting materials to yield the title compound as a white solid.

¹H NMR: (CDCl₃) δ 8.01 (s,1H), 7.75 (d, J=7.5 Hz, 1H), 7.62 (d, J=7.5 Hz, 1H), 6.91(br, s, 1H), 3.55 (abq, J=12.5 Hz, 1H), 2.60 (abq, J=12.5 Hz, 1H), 1.55 (s, 3H). MS (m/z): MH⁺308.

EXAMPLE 9 2-(3-Methyl-3,4-dihydro-2H-pyrazol-3-yl)-7-trifluoromethyl-3H-quinazolin-4-one

Following the procedure in Example 7, using 2-isopropenyl-7-trifluoromethyl-3H-quinazolin-4-one and TMSCHN₂ as starting materials yielded the title compound as a white solid.

¹H NMR: (CDCl₃) δ 10.70 (br, s, 1H), 8.35 (d, J=8.0 Hz, 1H), 7.95 (s, 1H), 7.65 (d, J=7.5 Hz, 1H), 3.25 (abq, J=10.5 Hz, 1H), 1.75 (s, 3H). MS (m/z): MH⁺297.

EXAMPLE 10 5-(6-Chloro-4-oxo-3,4-dihydro-quinazolin-2-yl)-5-methyl-4,5-dihydro-1H-pyrazole-3-carboxylic acid ethyl ester

Following the procedure in Example 7, using 6-Chloro-2-isopropenyl-3H-quinazolin-4-one and diazo ethyl acetate as starting materials yielded the title compounds as a white solid.

¹H NMR: (CDCl₃) δ 8.25 (s, 1H), 7.75 (d, J=7.0 Hz, 1H), 7.55 (d, J=7.5 Hz, 1H), 7.00 (s, 1H), 4.35 (q, J=9.5 Hz, 2H), 3.60 (abq, J=10.5 Hz, 1H), 3.25 (abq, J=10.5 Hz, 1H), 1.75 (s, 3H), 1.40 (q, J=9.5 Hz, 3H). MS (m/z):

MH⁺335.

EXAMPLE 11 Potassium Channel Assay

TE671 human medulloblastoma cells were obtained from ATCC and grown in Dulbecco's modified Eagle's medium (DMEM) supplemented with 10% fetal bovine serum, 100 U/ml penicillin and 100 U/ml streptomycine.

The day before testing, the cells were plated in black 96-well plates at 50K/well. On the day of testing, the growth media was removed, then 100 μl of FLIPR buffer (20 mM HEPES, 120 mM NaCl, 2 mM KCl, 2 mM CaCl₂, 1 mM MgCl₂, 5 mM Glucose) and 100 μl of Membrane Potential Assay Dye (Molecular Devices) dissolved in FLIPR buffer were added to each well. The cells were incubated at room temperature for 15 to 30 min.

The effect of test compounds on KATP channels were evaluated on a fluorometric imaging plate reader (FLIPR, Molecular Devices) at room temperature. After a baseline period, 50 μl of 5× stock solution of test compound prepared in FLIPR buffer was added and fluorescent change was monitored for 3 minutes. After this reading, glyburide, a KATP channel blocker, was added to a final concentration of 5 μM to check the specificity of the test compound as a KATP channel openers. Hyperpolarization resulting from KATP channel opening was observed as a decrease in fluorescent intensity.

Representative compounds of the present invention were tested according to the procedure described above, with results as listed in Table 2 below. Test compound activity was determined as the percent. A compound was designated as active if it produced greater than or equal to 10% response at 30 μM. A compound was designated as inactive if it produced less than 10% response at 30 μM.

TABLE 2 ID No response 1 active 2 active 3 active 4 active

EXAMPLE 12

As a specific embodiment of an oral composition, 100 mg of the compound prepared as in Example 7 is formulated with sufficient finely divided lactose to provide a total amount of 580 to 590 mg to fill a size O hard gel capsule.

While the foregoing specification teaches the principles of the present invention, with examples provided for the purpose of illustration, it will be understood that the practice of the invention encompasses all of the usual variations, adaptations and/or modifications as come within the scope of the following claims and their equivalents. 

1. A compound of formula I:

wherein: R¹ is selected from the group consisting of hydrogen, halogen, C₁₋₄ alkyl, halogenated C₁₋₄alkyl, CN and NO₂; R² is selected from the group consisting of hydrogen, halogen, C₁₋₄ alkyl, halogenated C₁₋₄alkyl, CN and NO₂; R³ is selected from the group consisting of hydrogen and C₁₋₄ alkyl; and R⁴ is selected from the group consisting of hydrogen, C₁₋₄ alkyl, halogenated C₁₋₄alkyl, phenyl and —C(O)O—C₁₋₄alkyl; or a pharmaceutically acceptable salt thereof.
 2. A compound as in claim 1, wherein R¹ is selected from the group consisting of hydrogen, bromo, chloro and cyano; R² is selected from the group consisting of hydrogen and trifluoromethyl; R³ is methyl; and R⁴ is hydrogen and C(O)—O-Et.
 3. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of claim
 1. 4. A process for making a pharmaceutical composition comprising mixing a compound of claim 1 and a pharmaceutically acceptable carrier.
 5. A method of treating a disorder related to ion channels, comprising administering, to a subject in need thereof, a therapeutically effective amount of the compound of claim
 1. 6. The method of claim 5, wherein the ion channel is a potassium ion channel.
 7. The method of claim 5, wherein the ion channel is an ATP-sensitive potassium ion channel.
 8. The method of claim 5, wherein the disorder related to ion channels is selected from the group consisting of urinary incontinence, overactive bladder, hypertension, erectile dysfunction, female sexual disorders, dysmenorrhea, irritable bowl syndrome, airway hyperactivity, epilepsy, stroke, Alzheimer's disease, Parkinson's disease, myocardial injury, coronary artery disease, hair loss and baldness.
 9. The method of claim 5, wherein the disorder related to ion channels is selected from the group consisting of urinary incontinence and overactive bladder.
 10. A method of treating a disorder selected from the group consisting of urinary incontinence, overactive bladder, hypertension, erectile dysfunction, female sexual disorders, dysmenorrhea, irritable bowl syndrome, airway hyperactivity, epilepsy, stroke, Alzheimer's disease, Parkinson's disease, myocardial injury, coronary artery disease, hair loss and baldness, comprising administering, to a subject in need thereof, a therapeutically effective amount of the composition of claim
 2. 